Oncolytic poliovirus for human tumors

ABSTRACT

Human clinical use of a chimeric poliovirus construct has demonstrated excellent anti-tumor effect. The mechanism of action is believed to involve both viral oncolysis as well as immune recruitment, both of which lead to necrosis in the area of the tumor. No adverse effects have been observed.

This invention was made using funds provided by the United Statesgovernment. The U.S. government retains certain rights according to theterms of grants from the National Institutes of Health R01 CA87537, P50NS20023, R01 CA124756, and R01 CA140510.

TECHNICAL FIELD OF THE INVENTION

This invention is related to the area of anti-tumor therapy. Inparticular, it relates to oncolytic virus anti-tumor therapy.

BACKGROUND OF THE INVENTION

PVS-RIPO is an oncolytic poliovirus (PV) recombinant. It consists of thelive attenuated type 1 (Sabin) PV vaccine containing a foreign internalribosomal entry site (IRES) of human rhinovirus type 2 (HRV2). The IRESis a cis-acting genetic element located in the 5′ untranslated region ofthe PV genome, mediating viral, m⁷G-cap-independent translation.

PVS-RIPO oncolytic therapy has been reported in tissue culture assays(6, 7, 10, 15-17) and in animal tumor models, but not in clinical trialsin humans. Because of the differences between tissue culture, animalmodels, and humans, efficacy is unpredictable. Moreover, viralpreparations used in pre-clinical studies are often impure, so that anyactivity cannot be attributed to the agent under investigation.

The art provides no examples of oncolytic viral agents in whichbiological activity in tumor models correctly predicted efficacy inpatients. The reason for this is that oncolytic viral therapy is theresult of a complex, triangular relationship between (a) the infectedmalignant cells, (b) the non-malignant tumor microenvironment, and (c)the host immune system. A system of such complexity and intricacy hasnot been recreated in any animal model.

There is a continuing need in the art to identify and develop effectiveanti-cancer treatments for humans, particularly for patients with braintumors.

SUMMARY OF THE INVENTION

According to one aspect of the invention a method is provided fortreating a human harboring a solid tumor which expresses NECL5 (CD155,HVED, Nec1-5, PVS, TAGE4; nectin-like 5; nectin-like protein 5). Achimeric poliovirus construct is administered directly to the tumor inthe human. The chimeric poliovirus comprises a Sabin type I strain ofpoliovirus with a human rhinovirus 2 (HRV2) internal ribosome entry site(IRES) in said poliovirus' 5′ untranslated region between saidpoliovirus' cloverleaf and said poliovirus' open reading frame.

These and other embodiments, which will be apparent to those of skill inthe art upon reading the specification, provide the art with methods oftreating tumors, including brain tumors.

BRIEF DESCRIPTION OF THE DRAWINGS

FIGS. 1A-1B (formerly FIG. 8.) Intratumoral PVS-RIPO infusion inducesgradual tumor regress. FIG. 1A. Tumor volumes upon mock (□) or PVS-RIPO(▪) treatment. FIG. 1B. Average virus recovery from tumors at theindicated intervals.

FIG. 2 (formerly FIG. 12). MRI from Apr. 16, 2012. Axial, postcontrast,T1-weighted MRI showing disease progression.

FIG. 3 (formerly FIG. 13). MRI from May 9, 2012. Axial, postcontrast,T1-weighted MRI obtained pre-infusion of PVS-RIPO.

FIG. 4 (formerly FIG. 14). MRI from May 11, 2012. Axial, postcontrast,T1-weighted MRI showing distribution of Gd-DTPA contrast and-presumably- PVS-RIPO within the brain.

FIG. 5 (formerly FIG. 15). MRI from Jun. 6, 2012. Axial, postcontrast,T1-weighted MRI showing disease stability.

FIG. 6 (formerly FIG. 16). MRI from Jul. 9, 2012. Axial, postcontrast,T1-weighted MRI revealed concerns for disease progression.

FIG. 7 (formerly FIG. 17). 18-FDG PET scan from Jul. 11, 2012. Theresults suggest the absence of hypermetabolic activity in the area ofconcern on MRI.

DETAILED DESCRIPTION OF THE INVENTION

The inventors have developed a viral construct for use in humans.Previously, laboratory grade preparations of the viral construct havebeen tested in cell culture and in animal models. But these tests arenot sufficient to attribute any effect to the viral construct itself,rather than other elements in the crude, laboratory grade preparations.Moreover, as is well known in the art, cell culture and animal modelsare not predictive of efficacy in humans.

Because the poliovirus is a potential disease agent, extra precautionsmust be taken to ensure that disease-causing agents are not introducedto the subjects. Using good manufacturing procedures and purifications,a preparation was made that was sufficiently pure to permit introductioninto humans in a trial.

Any technique for directly administering the preparation to the tumormay be used. Direct administration does not rely on the bloodvasculature to access the tumor. The preparation may be painted on thesurface of the tumor, injected into the tumor, instilled in or at thetumor site during surgery, infused into the tumor via a catheter, etc.One particular technique which may be used is convection enhanceddelivery.

Any human tumor can be treated, including both pediatric and adulttumors. The tumor may be in any organ, for example, brain, prostate,breast, lung, colon, and rectum, Various types of tumors may be treated,including, for example, glioblastoma, medulloblastomas, carcinoma,adenocarcinoma, etc. Other examples of tumors include, adrenocorticalcarcinoma, anal cancer, appendix cancer, grade I (anaplastic)astrocytoma, grade II astrocytoma, grade III astrocytoma, grade IVastrocytoma, atypical teratoid/rhabdoid tumor of the central nervoussystem, basal cell carcinoma, bladder cancer, breast sarcoma, bronchialcancer, bronchoalveolar carcinoma, cervical cancer, craniopharyngioma,endometrial cancer, endometrial uterine cancer, ependymoblastoma,ependymoma, esophageal cancer, esthesioneuroblastoma, Ewing's sarcoma,extracranial germ cell tumor, extragonadal germ cell tumor, extrahepaticbile duct cancer, fibrous histiocytoma, gall bladder cancer, gastriccancer, gastrointestinal carcinoid tumor, gastrointestinal stromaltumor, gestational trophoblastic tumor, gestational trophoblastic tumor,glioma, head and neck cancer, hepatocellular cancer, Hilarcholangiocarcinoma, hypopharyngeal cancer, intraocular melanoma, isletcell tumor, Kaposi sarcoma, Langerhans cell histiocytosis, large-cellundifferentiated lung carcinoma, laryngeal cancer, lip cancer, lungadenocarcinoma, malignant fibrous histiocytoma, medulloepithelioma,melanoma, Merkel cell carcinoma, mesothelioma, endocrine neoplasia,nasal cavity cancer, nasopharyngeal cancer, neuroblastoma, oral cancer,oropharyngeal cancer, osteosarcoma, ovarian clear cell carcinoma,ovarian epithelial cancer, ovarian germ cell tumor, pancreatic cancer,papillomatosis, paranasal sinus cancer, parathyroid cancer, penilecancer, pharyngeal cancer, pineal parenchymal tumor, pineoblastoma,pituitary tumor, pleuropulmonary blastoma, renal cell cancer,respiratory tract cancer with chromosome 15 changes, retinoblastoma,rhabdomyosarcoma, salivary gland cancer, small cell lung cancer, smallintestine cancer, soft tissue sarcoma, squamous cell carcinoma, squamousnon-small cell lung cancer, squamous neck cancer, supratentorialprimitive neuroectodermal tumor, supratentorial primitiveneuroectodermal tumor, testicular cancer, throat cancer, thymiccarcinoma, thymoma, thyroid cancer, cancer of the renal pelvis, urethralcancer, uterine sarcoma, vaginal cancer, vulvar cancer, and Wilms tumor.

Optionally, patients may be stratified on the basis of NECL5 expression.This can be assayed at the RNA or protein level, using probes, primers,or antibodies, for example. The NECL5 expression may guide the decisionto treat or not treat with the chimeric poliovirus of the presentinvention. The NECL5 expression may also be used to guide theaggressiveness of the treatment, including the dose, frequency, andduration of treatments.

Treatment regimens may include, in addition to delivery of the chimericpoliovirus construct, surgical removal of the tumor, surgical reductionof the tumor, chemotherapy, biological therapy, radiotherapy. Thesemodalities are standard of care in many disease states, and the patientneed not be denied the standard of care. The chimeric poliovirus may beadministered before, during, or after the standard of care. The chimericpoliovirus may be administered after failure of the standard of care.

Applicants have found that the clinical pharmaceutical preparation ofthe chimeric poliovirus has admirable genetic stability and homogeneity.This is particularly advantageous as the poliovirus is known to behighly mutable both in culture and in natural biological reservoirs. Anysuitable assay for genetic stability and homogeneity can be used. Oneassay for stability involves testing for the inability to grow at 39.5degrees C. Another assay involves bulk sequencing. Yet another assayinvolves testing for primate neurovirulence.

While applicants do not wish to be bound by any particular mechanism ofaction, it is believed that multiple mechanisms may contribute to itsefficacy. These include lysis of cancer cells, recruitment of immunecells, and specificity for cancer cells. Moreover, the virus isneuro-attenuated.

The above disclosure generally describes the present invention. Allreferences disclosed herein are expressly incorporated by reference. Amore complete understanding can be obtained by reference to thefollowing specific examples which are provided herein for purposes ofillustration only, and are not intended to limit the scope of theinvention.

EXAMPLE 1

Animal tumor models. An IND-directed efficacy trial of PVS-RIPO wasconducted in the HTB-15 GBM xenograft model in athymic mice. PVS-RIPO(from the clinical lot) was administered at the ‘mouse-adjusted’,FDA-approved max. starting dose [the FDA-approved max. starting dose(10e8 TCID) was adjusted for the reduced tumor size in mice (to 6.7×10e6TCID)]. Delivery mimicked the intended clinical route, i.e., slowintratumoral infusion. Under these conditions, PVS-RIPO induced completetumor regress in all animals after 15 days (FIG. 8A). While virus wasrecovered from treated tumors until day 10, the levels were modest atbest, indicating that direct viral tumor cell killing alone cannotaccount for the treatment effect (FIG. 8B)

Evidence from animal tumor models suggests that intratumoral inoculationof PVS-RIPO causes direct virus-induced tumor cell killing and elicits apowerful host immunologic response against the infected/killed tumor (3,7, 10). The response to virus infusion is characterized by a strong,local inflammatory response, leading to immune infiltration of thetumor. Eventually the slow tissue response to PVS-RIPO infusion leads tothe demise of the tumor mass and its replacement by a scar.

EXAMPLE 2

Clinical trials. IND no. 14,735 ‘Dose-finding and Safety Study ofPVSRIPO Against Recurrent Glioblastoma’ was FDA-approved on Jun. 19,2011 and IRB-approved on Oct. 27, 2011. A phase I/II clinical trial inpatients with recurrent glioblastoma (GBM) (NCT01491893) is currentlyenrolling patients.

Two human subjects have so far been treated with PVS-RIPO perIRB-approved protocol. Preliminary findings from the first subject aredescribed in Example 3.

EXAMPLE 3

Preliminary findings with first human subject. The patient is a21-year-old female nursing student diagnosed with a right frontal GBM(WHO grade IV). She was first diagnosed in June 2011, at the age of 20years, following a history of severe headaches and unsuccessfultreatment for a suspected sinus infection. Brain imaging was obtained onJun. 17, 2011 and showed a large right frontal mass, measuring ˜5×6 cm.She underwent a subtotal resection of the right frontal mass on Jun. 22,2011, with pathology confirming GBM (WHO grade IV). Given the young ageof the patient, her excellent performance status and the subtotal tumorresection, it was decided to treat her aggressively with a combinationof six weeks of radiation therapy with concurrent Temodar chemotherapyat 75 mg/m² by mouth daily and bevacizumab (antiangiogenic agent)administered every 2 weeks. The patient completed six weeks of treatmenton Sep. 18, 2011. On Oct. 3, 2011, the patient initiated adjuvanttherapy with monthly, five-day Temodar chemotherapy in addition tobevacizumab 10 mg/kg every two weeks.

On Apr. 16, 2012, the patient presented to clinic after havingexperienced her first generalized seizure, which occurred in her sleep.By that time, she had completed six months of the combination of Temodarand bevacizumab. She had attributed the seizure to increased stress atschool, as she was completing a degree to become a pediatric oncologynurse, despite her diagnosis of GBM and ongoing chemotherapy treatment.The brain MRI obtained on that day showed tumor recurrence, with a newnodular enhancement along the medial aspect of the resection cavity(FIG. 12).

The patient was offered multiple treatment options, but elected topursue the PVS-RIPO clinical trial. Following her first generalizedseizure, she was initiated on Keppra, but forgot to take it on occasionand because of this and the known tumor recurrence, the patientexperienced a second generalized seizure in her sleep on May 6, 2012.She went back to her baseline neurologic condition and was worked up toenroll on protocol.

A follow-up MRI was obtained on May 9, 2012 (FIG. 13), before thepatient underwent infusion of PVS-RIPO on May 11, 2012 with theFDA-approved max. starting dose (10e8) by the intended clinical deliverymethod (convection-enhanced, intratumoral infusion of 3 mL of virussuspension containing the contrast Gd-DTPA over 6 hrs; see Example 4)and experienced no neurologic or other complications related to this.

An MRI obtained immediately after completion of the infusion documentsthe distribution of the infusate (FIG. 14).

Our research team followed up on the patient on a weekly basis and shewas seen in clinic two weeks post infusion, at which time she denied anynew neurologic symptoms, seizure recurrence, fatigue, shortness ofbreath or weakness. She again was evaluated in clinic on Jun. 7, 2012and her physical and neurological conditions remained normal. The brainMRI obtained at that visit showed stability of the disease (FIG. 15).

The patient was seen in clinic on Jul. 9, 2012. Once more, she deniedany new neurologic symptoms, including the absence of any recurrentseizure activity since the seizure observed on May 6, 2012, prior toPVS-RIPO infusion. She also reported that her mood was good, that shewas content with her progress in nursing school, feeling that she isable to focus in school much better since after her infusion. She wasalso excited by her move with two roommates and by the fact that she isable to exercise regularly. Her brain MRI obtained on that day showed aslightly increased mass effect and minimal increase in superior linearenhancement, concerning for progression of disease (FIG. 16).

In view of worrisome radiographic changes with no clinical worsening, wedecided to obtain an 18-FDG PET scan. The 18-FDG PET scan demonstratedhypometabolic activity in the area of concern on the MRI, suggestive ofa necrotic process (treatment response effect; FIG. 17). The PET scanfrom July 9 suggests the absence of viable tumor. After discussion withthe patient and her mother, it was decided to continue to follow thepatient from a clinical and radiographic standpoint.

In check-ups on August 27 and October 22 the patient denied any newneurologic symptoms, including the absence of any seizure activity sincethe seizure on May 6, 2012 (prior to PVS-RIPO infusion). The patientreports improved cognitive/memory function, motor function (exercise).As of October 26, the patient is neurologically normal.

Because of the favorable radiographic presentation at August 27, a PETscan was not ordered. The patient was re-scanned on October 22 and therewas a quantifiable radiographic response.

An MRI/PET overlay demonstrates the absence of signal from the generalarea of the tumor recurrence.

EXAMPLE 4

Convection infusion. Preoperatively the BrainLab iPlan Flow system isused to plan catheter trajectories based on predicted distributionsusing information obtained from a preoperative MRI.

This invention uses one mM of gadolinium, along with ¹²⁴I-labeled humanserum albumin to a surrogate tracer to identify the distribution of thepoliovirus. This could be used for other drug infusions as well. Thegadolinium and radio-labeled albumin is co-infused with the drug andvarious MRI sequences and PET imaging are used to quantify thedistribution.

The entire volume of the agent to be delivered will be pre-loaded into asyringe by the investigational pharmacist and connected to the catheterunder sterile conditions in the operating room or the NICU just prior tobeginning of infusion. Due to the complexity of scheduling all of thenecessary components for the infusion (operating room time, pharmacytime, and radiology appointments), a +1 day window has been built in tothe study for the study drug infusion. This means that the infusion isallowed to start the following day after the biopsy/catheter placement.This will still be considered “day 0” in regards to the protocol and thetiming of the subsequent events. At the time of virus injection,emergency drugs, including epinephrine and diphenhydramine will beavailable and the neurologic status, oxygen saturation, and cardiacrhythm will be monitored. Drug infusion will occur in the Neuro-SurgicalIntensive Care Unit (NSCU) so that all other emergency facilities willbe available. Patients will be treated with a prophylactic antibioticsuch as nafcillin, a second-generation cephalosporin or vancomycinstarting with the induction of anesthesia for the catheter placement.

Based on our own experience, previously published reports (19) and IRB-and FDA-approved trials using similar infusion techniques (IRB#4774-03-4R0), patients will be infused at a rate of 500 μL/hr. AMedfusion 3500 infusion pump will be pre-programmed to a delivery rateof 500 μL/hr. The agent (which will be in a total volume of 10 mL toaccount for ‘dead-space’ of 3.3723 mL in the infusion system) will beloaded in a 20 mL syringe into the syringe pump at the initial onset toavoid any interruptions in the infusion. The total amount of theinoculum delivered to the patient will be 3 mL. The catheter itself (30cm length, 1 mm interior diameter) cannot be preloaded with virussuspension. Therefore, the initial ˜250 μL of infusion will bepreservative-free salinein the ‘dead-space’ of the indwelling catheter.To account for this, the infusion pump will be programmed for deliveryof 3.250 mL. The infusion will be performed using a Medfusion 3500(Medex, Inc., Duluth, Ga.) syringe infusion pump. The virus injectionprocedure will be completed within 6.5 hrs. The catheter will be removedimmediately following the delivery of PVSRIPO.

The infusion catheter (PIC 030) and infusion tubing (PIT 400) will besupplied by Sophysa, Inc. (Crown Point, Ind.). The Infusion Catheter Kitis a 30 cm clear, open-ended catheter (1.0 mm ID/2.0 mm OD) with 1 cmmarkings for 20 cm. The catheter comes with a 30 cm stainless steelstylet, a barbed female luer lock with cap and a stainless steel trocar.The Infusion Tubing Kit consists of a 3-way stopcock connector with airfilter, 4 m of microbore tubing with antisiphon valve, a red, vented capand a white luer lock cap. The catheter products are packaged sterileand non-pyrogenic and are intended for single (one-time) use only. Theinfusion will be performed using a Medfusion 3500 (Medex, Inc. Duluth,Ga.) syringe infusion pump.

REFERENCES

The disclosure of each reference cited is expressly incorporated herein.

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1. A method of treating a human harboring a solid tumor which expressesNECL5 (nectin-like protein 5), said method comprising the steps of:administering directly to the tumor in the human a chimeric poliovirusconstruct comprising a Sabin type I strain of poliovirus with a humanrhinovirus 2 (HRV2) internal ribosome entry site (IRES) in saidpoliovirus' 5′ untranslated region between said poliovirus' cloverleafand said poliovirus' open reading frame.
 2. The method of claim 1wherein convection enhanced delivery is used to administer the chimericpoliovirus construct.
 3. The method of claim 1 wherein the solid tumoris a glioblastoma.
 4. The method of claim 1 wherein the solid tumor is aprostate tumor.
 5. The method of claim 1 wherein the administration isintracerebral.
 6. The method of claim 1 wherein the solid tumor is amedulloblastoma.
 7. The method of claim 1 wherein the solid tumor is abreast tumor.
 8. The method of claim 1 wherein the solid tumor is a lungtumor.
 9. The method of claim 1 wherein the solid tumor is a colorectaltumor.
 10. The method of claim 1 wherein the administration isintracerebral infusion with convection enhanced delivery.
 11. The methodof claim 10 wherein the administration is stereotactically guided. 12.The method of claim 1 wherein the human is an adult.
 13. The method ofclaim 1 wherein the human is a child.
 14. The method of claim 12 whereinconcurrent or serial chemotherapy is administered to the human.
 15. Themethod of claim 13 wherein concurrent or serial radiotherapy isadministered to the human.
 16. The method of claim 1 wherein the solidtumor is subjected to surgical removal before or after administering thenonpathogenic, oncolytic, poliovirus.
 17. The method of claim 1 whereinprior to the step of administering the solid tumor is tested forexpression of NECL5.
 18. A method of treating a human harboring a solidtumor which expresses NECL5 (nectin-like protein 5), said methodcomprising the steps of: testing a solid tumor to ascertain that itexpresses NECL5; administering directly to the tumor in the human achimeric poliovirus construct comprising a Sabin type I strain ofpoliovirus with a human rhinovirus 2 (HRV2) internal ribosome entry site(IRES) in said poliovirus' 5′ untranslated region between saidpoliovirus' cloverleaf and said poliovirus' open reading frame, whereinthe administering is stereotactically guided, intracerebral infusionwith convection enhanced delivery.
 19. A clinical pharmaceuticalpreparation of a chimeric poliovirus construct, comprising: a Sabin typeI strain of poliovirus with a human rhinovirus 2 (HRV2) internalribosome entry site (IRES) in said poliovirus' 5′ untranslated regionbetween said poliovirus' cloverleaf and said poliovirus' open readingframe; and gadolinium.
 20. The clinical pharmaceutical preparation ofclaim 19 wherein the gadolinium is chelated with diethylene triaminepentaacetic acid (DPTA).
 21. The clinical pharmaceutical preparation ofclaim 19 further comprising human serum albumin.
 22. The clinicalpharmaceutical preparation of claim 21 wherein the human serum albuminis radiolabeled.
 23. The clinical pharmaceutical preparation of claim 22wherein the human serum albumin is radiolabeled with ¹²⁴I.
 24. A methodof delivering a clinical pharmaceutical preparation to a solid tumor ina human, comprising: administering via convection enhanced infusionthrough a single intratumoral catheter, a dose of a poliovirus constructwithin 6.5 hours, wherein said poliovirus construct is in a clinicalpharmaceutical preparation comprising a Sabin type I strain ofpoliovirus with a human rhinovirus 2 (HRV2) internal ribosome entry site(IRES) in said poliovirus' 5′ untranslated region between saidpoliovirus' cloverleaf and said poliovirus' open reading frame; andgadolinium.
 25. The method of claim 24 wherein the tumor is a braintumor.
 26. The method of claim 24 wherein the tumor is a glioblastomamultiforme.
 27. The method of claim 24 wherein the tumor is a pancreatictumor.
 28. The method of claim 24 wherein the tumor is a prostate tumor.29. The method of claim 24 wherein the dose is delivered over a 6 hourperiod.
 30. The method of claim 24 wherein the tumor expresses NECL5.31. The method of claim 24 further comprising the step of testing thesolid tumor to ascertain that it expresses NECL5.
 32. The method ofclaim 1 wherein the chimeric poliovirus construct is in a clinicalpharmaceutical preparation comprising gadolinium.
 33. The method ofclaim 18 wherein the chimeric poliovirus construct is in a clinicalpharmaceutical preparation comprising gadolinium.
 34. The method ofclaim 1 wherein the method further comprises administering a biologicaltherapy.
 35. The method of claim 18 wherein the method further comprisesadministering a biological therapy.
 36. The method of claim 24 whereinthe method further comprises administering a biological therapy.